Standing by. We welcome you to Syndax Q4 and end of year 2018 earnings call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require operator assistance during today's conference, please press star then zero on your touchtone telephone. As a reminder, this conference call may be recorded. I would now like to turn the conference over to Melissa Forst with Argot Partners. Please go ahead.
Thank you. Welcome, thank you to those of you joining us today for Syndax's Q4 and 2018 full year financial and operating results conference call. Joining us this afternoon for prepared remarks will be Dr. Briggs Morrison, Chief Executive Officer, and Rick Shea, Chief Financial Officer.
Also joining us on the call today for the question and answer session are Michael Metzger, President and Chief Operating Officer, Dr. Michael Meyers, Chief Medical Officer, and Dr. Peter Ordentlich, Chief Scientific Officer. This call is being accompanied by a slide deck that has been posted on the company's website, I'd please ask you to turn to the forward-looking statements on slide two. Before we begin, I would like to remind you that any statement made during this call that is not historical is considered to be forward-looking in nature per the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these statements as a result of various factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K, as well as other reports filed with the SEC. Any forward-looking statements represent the company's views as of today, 7 March 2019 only. A replay of this call will be available on the company's website, www.syndax.com, following the call. With that, I am pleased to turn the call over to Dr. Morrison.
Thank you very much, Melissa, thank you to everyone who's joining us on today's call webcast. As we closed out 2018 and entered 2019, we took the time to look back at what this management team has accomplished over the past three and a half years.
Our goal has been to build a pipeline of opportunities that would allow us to reach our mission, that would allow us to realize a future in which people with cancer live longer and better than ever before. As we were closing out 2018, we concluded that we have too many opportunities for a company of our size and resources. Through conversations with physicians, scientists, advisors, and members of our board, we've prioritized our portfolio.
The work was difficult. We've had many passionate advocates inside and outside our company for every one of our active programs. We believe that all our active programs have potential to benefit patients. Yet, we had to choose the ones we thought had the most potential. Today, I'm going to share with you the results of that prioritization effort and explain our reasoning.
Slide three provides a high-level summary of our prioritization effort. As we progress through 2019, we'll be focusing our resources on two incredibly exciting opportunities. First, we are anticipating a positive readout of E2112, Phase Iii trial of Entinostat in hormone receptor-positive breast cancer, and the subsequent filing of our first NDA and the corresponding launch of our first product.
I want to emphasize that a positive OS trial in hormone receptor-positive, HER2 negative breast cancer would be a landmark result that would be transformative for Syndax and its shareholders. We believe the Entinostat opportunity in hormone receptor-positive breast cancer carries blockbuster potential. This is an important opportunity for us and it will require our focus and resources.
Second, we anticipate a Q2 filing of the IND for SNDX-5613, our potential first and best-in-class targeted agent for the treatment of mixed lineage leukemias, along with the rapid initiation of our broad 5613 clinical program. As we continue to learn more about the potential of 5613 in acute leukemia, we see this molecule becoming an additional and important value driver for our company.
We may have early clinical data from the program later this year. We believe that the breadth of indications we will investigate with SNDX-5613 represents a second completely distinct blockbuster opportunity. This too is an important opportunity for us and it will require our focus and resources. Given these two tremendous opportunities, we've chosen not to move forward at this time with our Entinostat KEYTRUDA combination trial in non-small cell lung cancer.
It's a very difficult decision for us given the strong data we have seen in our ENCORE 601 program in both non-small cell lung cancer and melanoma. Yet, we believe our near-term focus on E2112 and 5613 is the right thing to do for our company.
I will also note that we announced today that neither ENCORE 602 nor 603 met their primary endpoint. These results were not a material factor in our decision to refocus our resources. I will say more later about why we don't think the results of 602 and 603 inform our view of the non-small cell lung cancer and melanoma results.
Let me now turn to slide four and give you an update on Phase Iii trial of Entinostat in hormone receptor-positive, HER2 negative breast cancer, the first area of focus for 2019. Slide four again summarizes the trial design. The trial randomized 608 patients to exemestane plus placebo versus exemestane plus Entinostat. The focus of this trial is now clearly and unequivocally on overall survival. As we've noted before, OS interim analyses are done approximately every six months, so the next interim OS analysis will be around May and November of this year.
Positive outcome at any of these interim analyses, or upon achieving the final number of events needed to conclude the study, would allow us to file for regulatory approval based upon the terms of our special protocol assessment with FDA. The final analysis of this trial will be conducted once there are 410 survival events.
We don't know exactly when those 410 events will occur, but based upon modeling that we've done, we think that the final analysis could be November of this year, although it could drift into May of 2020. We remain very confident in the possibility that E2112 will achieve a survival benefit, and hence our decision to keep our focus on this opportunity.
Recall that it was Phase Ii os results that led to the granting of the breakthrough therapy designation by FDA. As I have summarized previously, based on the results of Phase II trial, combined with the statistical design of E2112, we always believed the OS endpoint was more likely to be positive than PFS in E2112. Hence, the fact that PFS did not achieve the very high pre-specified statistical hurdle does not in any way diminish our confidence in the possibility of achieving a survival benefit in E2112.
We also know that OS is the most valued endpoint for patients, physicians, regulators, and payers, and hence a positive OS trial would enable both rapid regulatory review and potentially rapid payer access. Slide five emphasizes the blockbuster potential for the Entinostat exemestane regimen to be the preferred agent after a CDK4/6 therapy for hormone receptor-positive, HER2-negative breast cancer.
We know that CDK4/6 therapies, most notably IBRANCE, are being used increasingly as first-line agents, but there's a clear desire to understand what therapies will be affected in a patient who has stopped responding to a CDK4/6 inhibitor. Our current estimate is that between 30% and 50% of patients in E2112 will have received a CDK4/6 inhibitor prior to entering the trial, and thus we will have a highly relevant data set in the post-CDK4/6 patient population.
This population of patients is relatively large, with an estimated 34,000 patients each year who go on to receive hormone therapy after failing first-line therapy and could therefore potentially be eligible to receive Entinostat. We're also very excited about the upcoming IND filing for our genetically targeted agent, SNDX-5613, and I would therefore like to spend some time describing that program for you now.
Slide six points out the similarity between our Menin program and other medicines that have been developed to attack fusion proteins that are a result of chromosomal rearrangements. The first example of a recurring chromosomal rearrangement in oncology was the so-called Philadelphia chromosome, which resulted in the BCR-ABL fusion protein and which led to the development of gleevec and other BCR-ABL inhibitors.
Since then, there have been additional examples where scientists have been able to develop medicines that specifically attack such fusion proteins that result from a chromosomal translocation, including medicines against EML4-ALK fusions, NTRK fusions, and RET fusions. These fusion proteins, which are the result of a chromosomal translocation, have been a very fruitful area of oncology drug development, given the strong evidence that the fusion protein is driving the cancer cell.
Development of such medicines is enabled by being able to precisely define the patients, leading to large treatment effects in specific patient populations and a rapid clinical development and regulatory path. I want to emphasize that our Menin program is an example of a targeted therapy that is designed based upon our understanding of a specific chromosomal rearrangement that leads to a specific fusion protein known to drive the leukemic process.
Slide seven shows a simplified view of the MLL-r fusion protein. The left half of the fusion protein comes from a protein called MLL1, and the right half of the fusion protein comes from another protein. The fusion protein never appears in a normal cell i t is only found in leukemic cells. The left half of the fusion protein binds to a protein called Menin, and our drug blocks that binding and hence blocks the ability of the fusion protein to work. This has been studied at the crystal structure level, as shown on the right panel of this slide.
Menin interaction is shown schematically on slide eight. On the left figure, you can see that the MLL1 fusion protein bound to Menin, assembling a large multi-unit machinery that causes abnormal production of a variety of proteins that cause leukemia. On the right figure, you can see that SNDX-5613 blocks the ability of the fusion protein to bind to Menin and stops the abnormal production of the downstream proteins that cause leukemia.
The cancer cell normally differentiates and dies. I want to again emphasize that 5613 is targeted to inhibiting the action of a specific fusion protein found only in cancer cells, which is like other medicines that have been designed to work against cancer-specific fusion proteins.
On slide nine, we summarize the status of this program. The IND is on track to be filed the Q2 of this year, with the Phase I/ii clinical program to begin soon thereafter. We will be enrolling adults with MLL-r leukemias, followed by children with MLL-r leukemias. We will also be enrolling adults with NPM1 mutant leukemia based upon very compelling preclinical data showing SNDX-5613 has promising activity in that disease as well, as was recently presented at ASH this past December.
I want to emphasize we see a rapid and straightforward clinical development path for SNDX-5613, like the path taken for patients with NTRK fusions or IDH1 mutations. We expect that the molecule should have single agent activity and it's quite possible we could observe clinical activity very early in the clinical development path, again, unlocking significant value for Syndax and its shareholders.
As we continue to learn more about the potential of 5613 in acute leukemia, we see this molecule becoming an additional and important value driver for our company. We therefore have chosen to focus our resources on developing this targeted therapy as rapidly as possible. Let me now turn to our ENCORE clinical trial program, in which we've tested Entinostat in combination with PD-1 pathway antagonists, either PD-1 antibodies or PD-L1 antibodies.
I remind investors that this program was set up as a signal-seeking program exploring different tumors that have different immunologic characteristics. We've also invested in looking for biomarkers that could predict clinical benefit. With today's announcement of the results of ENCORE 602 in triple-negative breast cancer and ENCORE 603 in ovarian cancer, we have now essentially completed this signal-seeking program.
Slide 10 shows the immunologic environment is quite different in different tumors, with lung cancer and melanoma often being infiltrated with T cells, colorectal cancer and triple-negative breast cancer being characterized as having T cells, but for some reason, they organize around the rim of the tumor and are excluded. Ovarian cancer being generally characterized with an absence of T cells.
We asked whether Entinostat would enhance the activity of PD-1 pathway antagonists in these different clinical settings based upon a variety of preclinical observations. It appears that the beneficial effect of Entinostat is evident in the inflamed tumors and not in the other immunologic settings. I think this is an important conclusion of our work.
Slide 11 summarizes our findings, w e've seen a strong signal of clinical benefit when Entinostat is combined with KEYTRUDA in patients with non-small cell lung cancer whose disease has progressed after both chemotherapy and a PD-1 antagonist. We've also identified a biomarker, the peripheral blood classical monocytes, that appears to predict clinical benefit in this population of patients.
In addition, we've seen a strong signal of clinical benefit when Entinostat is combined with KEYTRUDA in patients with melanoma whose disease has progressed after both a PD-1 inhibitor and a CTLA-4 inhibitor. Updates on both of these exciting programs will be presented at AACR. Indeed, we've been notified that each of these will be the subject of an oral presentation.
Based on the data in our ENCORE studies, we previously communicated our intention to initiate a registration study in a biomarker-defined subset of non-small cell lung cancer patients, the ENCORE 607 study. We believe the ENCORE 601 data also warrants moving forward in melanoma. We will be reviewing the updated data to be presented at AACR with our partners and remain open to partnering opportunities with Entinostat in both non-small cell lung cancer and melanoma.
However, as a result of our prioritization efforts, we have decided to defer the initiation of the non-small cell lung cancer 607 study, as well as any melanoma registration study, pending the results of E2112. Rick will discuss the impact of this decision on our financial guidance. Let me now briefly turn to slide 12 and SNDX-6352, our potential best-in-class monoclonal antibody therapy targeting the CSF1 receptor.
As you may recall, the monotherapy multiple ascending dose study in cancer patients is ongoing, as is the combination of 6352 with Imfinzi, AZ's PD-L1 inhibitor. We anticipate selecting a Phase Ii dose next quarter.
Our chronic GVHD trial is also underway, we anticipate initial efficacy data from that trial in the second half of the year. Finally, slide 13 summarizes how the transactions that we have completed to acquire both SNDX-6352 and SNDX-5613 prove that we have an ability to strategically expand our pipeline.
Our management team and board have established relationships that allow us to identify quality, differentiated assets, the extensive clinical development experience of our team gives us a competitive advantage in closing agreements. We continue to expend significant effort in this area, we consider this capability to be a core strength of our company. With that, I'll turn it over to Rick for the financial update.
Thank you, Briggs. The results of our operations for Q4 and full year 2018 and the comparison to the prior year periods are included in our press release, so I won't repeat them in these remarks. Additional financial details are available in our Form 10-K, which we have just filed this afternoon.
Turning to slide 14, we ended 2018 with $80.9 million in cash and 26.8 million shares outstanding. The net change in cash for Q4 was a decrease of $8.7 million t he operating cash burn of $14.8 million was offset by $6.1 million of net proceeds from our ATM. We currently have $31 million available to sell off the ATM.
Looking ahead, slide 14 shows our updated financial guidance for both Q1 and for the full year of 2019. For the Q1 of 2019, we expect R&D expenses to be $11 million-$13 million, and total operating expenses to be $15 million-$17 million, which includes approximately $1.5 million of non-cash stock compensation expense.
For full year 2019, we expect R&D expenses of $46 million-$50 million and total operating expenses of $60 million-$64 million. Operating expenses for 2019 are expected to include non-cash stock compensation expense of $6 million, and interest income runs approximately $2 million o ur net cash burn for 2019 is expected to be $52 million-$56 million.
This projected cash burn for 2019 is approximately $8 million lower than our previous guidance due to the pause in initiating Entinostat IO registration studies in either non-small cell lung cancer or in melanoma, as Briggs discussed, and to further focusing our operating activities on our highest priority programs.
Our current cash, along with reduced spending, will allow us to operate the company to achieve key milestones for our prioritized programs, specifically OS results for E2112 and early proof of concept for SNDX-5613, our targeted Menin inhibitor. Now I'll turn the call back over to Briggs.
Thanks very much, Rick. I'd like to close our call with a clear summary of our company priorities. We believe that a positive OS result in E2112 would be transformative for Syndax and create significant shareholder value. Although we believe the final OS readout for E2112 could occur by the end of this year, we are prepared for a potential later final readout in mid-2020. We're also very excited about the prospects for SNDX-5613, our Menin MLL-r inhibitor.
We expect that the molecule could have single agent activity, and it's quite possible that we could observe clinical activity early in the clinical development path, again, unlocking significant value for Syndax. We are prepared to get through the initial proof of concept data from this program, which could take us into mid to late 2020.
We remain extremely excited about our data in lung cancer and melanoma. Updates from both of those programs will be the subject of oral presentations at AACR. We believe it is prudent to pause our further development spending in IO until such time that we receive the positive results of E2112. Rick has outlined our financing plans, and we want investors to be clear that we are not currently forecasting registration programs in lung cancer or melanoma in our financial guidance.
For SNDX-6352, we remain on track to select a Phase Ii dose in solid tumors in the Q2 of this year and anticipate having initial efficacy data in chronic GVHD later in the year. I continue to aggressively look for additional molecules or technologies to bring into our portfolio. I believe we have a proven track record of delivering on this pillar of our strategy, and I believe this is a core strength of our company.
As always, I would like to thank the team here at Syndax, our collaborators, and most importantly, the patients, trial sites, and investigators involved with our clinical programs. With that, I'd like to open the call for questions.
Thank you. Ladies and gentlemen, if you have a question at this time, please press the star then the one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. In order to prevent any background noise, we ask you to please place your line on mute once your question has been stated. Again, there is a star then one to ask a question. Our first question comes from the line of Christopher Marai with Nomura Instinet. Your line's now open.
Hi. Thanks for taking the question. I was wondering if you could help elaborate a little bit on the Phase Ii dose data that we might be seeing for SNDX-6352 in combo with the PD-L1. What other data are you going to provide there beyond a Phase Ii dose? Will you also look at target engagement measures, other measures around the, I guess, patient tumor microenvironment, et cetera? I have a follow-up t hank you.
Right C hris, this is Briggs. I think you've probably seen some of the PK/PD data that we presented from the normal healthy volunteers. We'll be confirming that in the combination trials with PD-1 and the Phase Ii dose. I think that's the main output.
We'll certainly be presenting data on both PK as well as important PD parameters such as CSF1 levels, IL34 levels, target engagement, monocyte depletion.
Okay.
Those will all go into a determination of what the appropriate RP2D is.
Great. That's very helpful. Then I guess just another one, if I may. Regarding the path forward for some of the Entinostat IO programs, I understand they're on hold, I guess that's pending the results of Entinostat in breast cancer. In the event that Entinostat does not produce an OS result in breast cancer, would you be open to reopening, reevaluating these programs, Entinostat specifically in the IO programs, or not? How should we think about that? Thank you.
Yeah. I think, Chris, our base assumption is that based on the Phase Ii data, that 2112 will be positive. We haven't really given too much guidance around what would happen if that wasn't the case and what we would do with the IO program.
Okay. Got it. Makes sense. Thank you very much.
Thank you. Our next question comes from the line of Chris Shibutani with Cowen. Your line's now open.
Great t hanks very much f or 5613, look forward to you guys introducing that into the clinic. Can you help us a little bit frame the opportunity? In particular, you talk about potential best-in-class and the absence of treatment so c ould you just give us a sense for the MLL rearranged as well as the NPM1 leukemias, what kind of percentage we believe of the AML populations these may be? And then when you're thinking about the initial monotherapy use, what line or what stage of clinical treatment are these patients that you're thinking about in these initial Phase I, II work that you're doing? Thanks.
Hi, Chris. Again, I think you nicely laid out, there are essentially three different populations that we have been talking about t here are the MLL-rearranged leukemias that occur in kids, which is generally ALL, and then there are the mixed lineage leukemias that occur in adults, which is generally AML.
For the pediatric ALL, the worldwide incidence is probably about 1,000 patients a year, about 10% of ALL. If you ever heard of an infant being born with ALL, about 80% of those are these MLL-rearranged leukemia so t hat is the pediatric ALL. In adult AML, it is about 6%-10% of AML, about 5,000 patients a year. The NPM1 mutant population represents about a third of all AML, that gives you some rough numbers around the size of the opportunity.
In terms of the patient population that we would study, of course, we would be studying relapse refractory patients in, again, pediatric MLL-rearranged leukemias, adult MLL-rearranged leukemias, and adult NPM1 mutant leukemias.
You make two statements on slide number nine, potential best in class. Can you help us understand what data you have seen so far, be it preclinical or anything early that would support how you are defining that? The path to market w e are certainly seeing in the AML, so much development of novel treatments over the last three to five years or so. You talk about standard screening protocols. In existence already are these mutations that are being screened for t hanks.
Sure. Again, I think, we are only aware of one other molecule that is approaching the clinic for this particular target w e really like our molecule, w e think it is very clean, very specific, very potent, and hence the hypothesis that it could be best in class. What was your second question?
Potential fast to market.
Oh, right.
Potential. You talk about.
Sure.
Standard screening. Is that-
Yep.
-in practice today?
Yes. I think, the short answer is yes, NPM1 mutations are standardly screened for in patients with leukemia. The MLL-r, again, it's a chromosomal rearrangement, whether you do even just a chromosomal spread or you do look specifically for it, these are identified today. What we've heard from all of our investigators, again, these will be relapse refractory patients, but they know at the time the patients are diagnosed that they have these genetic lesions, we don't think we'll have much problem identifying the patients that would be candidates for our therapy.
In terms of the background therapy, you say potential monotherapy benefit. Would we assume that these patients are not getting some of the standard, for instance, seven plus three chemo in the AML setting? Just clarify a little bit more what you mean by monotherapy.
Sure r ight. These would be relapse refractory patients. For AML, we would anticipate that they would have been treated with seven and three. For the MLL-r AMLs, they tend not to stay in remission very long, they'll have relapsed. We wouldn't be at all surprised if they hadn't received other therapies that are available, whether it's a FLT3 inhibitor, venetoclax, other things that are around for AML.
That's all up to the physician. They could come in just having relapse from their seven and three or some reinduction regimen, they would be relapse refractory patients. Again, I think from a single agent point of view, it's really what we're looking for is clinical activity as a single agent in patients who have relapse refractory disease. Not that different from what I think Agios did with their IDH1 inhibitor.
Okay. That's helpful w e'll look forward to the clinical progress with that program. Thank you.
Thank you.
Our next question comes from the line of Robert Hazlett with BTIG. Your line's now open.
Hi. Thanks for the question. This is actually Jay Colby on the line for Bert. I was just wondering, what would give you the confidence to resume development of Entinostat PD-1 combinations?
Jay, thanks very much for your question. This is really a sort of prioritization effort given the resources that we have available to us. It's not that we don't have confidence, and as I said, it's kind of interesting that we have two oral presentations at AACR so o bviously the organizers there thought that we had some pretty interesting data so, it's not that we don't have confidence in them, it's really just a prioritization around our resources. I should say when 2112 is positive, if we had more resources, we would go back and revisit these potential investments. At this point, they're not in our financial guidance.
Great. Okay, that's helpful. I guess on 5613, how should we think about trial size and maybe any other comments you can make on potential trial design here? and then how would you define showing proof of concept for the program? Thank you.
Sure w e probably won't say too much more about the details of the trial i think after the IND is approved and we have a clear, agreed-upon detailed trial design, then we'll talk more about it. I think in the AML space, the standard definition of efficacy is a complete response. We're looking for patients to have complete responses from their AML and a gain, I think if you look at the Agios story as a good surrogate for the kind of program we'd like to envision.
Thank you.
Thank you. Our next question comes from the line of David Lebowitz with Morgan Stanley. Your line's now open.
Thank you very much for taking my questions. Would you be able to, I guess, help run us through the reason why the Entinostat PD-1 combos might work in inflamed tumors in a better way than excluded versus not inflamed?
Yeah. David, thanks very much for the question. I'll let Peter Ordentlich take that question, our Chief Scientific Officer. Peter?
Yeah, thanks for that question. We think based on what we've learned, and we'll actually show some of this at AACR, that there's some preexisting priming or some type of immune activity required in order to see benefit with Entinostat and b ased on some of the gene expression work that we've done, particularly in the lung cancer cohort-
-we have some better understanding of what some of those resistance pathways may be and the way that Entinostat may be able to inhibit those and i t's just seems that in these harder-to-treat tumors where the immune activity in general seems to be low, like ovarian and triple-negative.
That we just may not have that preexisting signal for which Entinostat may be able to work on. I think that's reflected by the relatively low efficacy of the immune checkpoints overall in those types of tumors. I think it's a combination of existing resistance pathways that Entinostat can target, as well as some preexisting immune reactivity.
Thank you very much for that. I guess, if you could just run us back through, I know E2112 OS is coming up, the next analyses. Based on what occurred in Phase II trial, what is the, I guess, a similar timeframe as far as OS analyses that Phase III could theoretically conclude?
I think briefly, the trial could conclude at this upcoming readout in May, or it may require going to the full 410 events i think we're at that point in the evolution of the trial. Remember that there are also futility analyses, which the trial has continued to progress. Based upon that, it could be as early as May, or it may take till the final 410 event.
Thank you very much.
Thank you. Our next question comes from the line of Joel Beatty with Citi. Your line's now open.
Hi, thanks for taking the questions. The first one is about the focus on your pipeline i t looks like based on the press release, the emphasis is on E2112 file as well as the Menin program. I noticed the CSF1R program is not on that list. Could you maybe help us understand the difference in focus you see from the early stage CSF1R program compared with your focus on the Menin program?
Hi, Joel t hanks so much for the question. Again, I think we like both programs. The CSF1R program, the single agent work being done in GVHD will continue t here's not really new work or new resources we have to dedicate to that program, i t's not a large burden of our existing resources.
I think as we gear up for 5613, that is sort of new resources that we want to make sure we have in place and that people have a focus. And again, as I indicated in my prepared remarks, these diseases that are driven by chromosomal translocations tend to be quite fruitful so w e just want to really make sure we keep our focus on the Menin program.
I think if we see activity in GVHD, we'll again reevaluate the prioritization i think the prioritization work that we do is ongoing constantly as new data becomes available. I think that might help you in thinking about the decisions we've made.
Appreciate it. Another program on the E2112 trial. Still some uncertainty on when it will read out. I imagine that part of what affects that is the P values that are remaining compared with what's already been spent. Could you help us understand that and what P alpha is left and how it's split among the remaining potential readouts?
Yeah. I don't think we've ever disclosed what the thresholds are at each of the interim analyses. What we can say is that, you may remember, the trial was set up where 0.002 of the alpha went to PFS and 0.048 goes to OS. There is a very small amount of alpha that's spent on each of the interims, but we've never talked about what the actual threshold is for each of those interims.
Okay g ot it. Maybe one last question on partnering. It sounds like it's still an important focus for looking for additional assets. Could you help us, maybe just on a high level, what you're looking for, what would make one potential asset more attractive than another?
Yeah. I always joke with my team that the only molecules we want to license are ones that work. If it works, we'd be interested in it. I think we have a sort of a prioritization list of how we think about different molecules and interestingly, we set that prioritization list up a number of years ago when we first joined the company.
Tumors that are driven by chromosomal rearrangements and no infusion proteins was actually number one on our list, and that's why we were so excited when the Menin program became available. There are a variety of targets that we would be interested in, but I don't think I can say much more than that.
Got it. Thank you.
Thank you. Our next question comes from the line of Madhu Kumar with R.W. Baird. Your line's now open.
Yeah. Thanks for taking our questions. First one, thinking about E2112. You previously talked about preclinical data for CDK4/6 drugs, their pre-treatment not affecting Entinostat plus exemestane responsiveness. Kind of thinking about the flip side, have you examined whether later line chemotherapies in HR-positive breast cancer respond differently after Entinostat plus exemestane treatment versus exemestane alone?
I don't think, Peter, the only place we'd be able to look at that was from Phase II data, I don't know, either Peter or Michael, if you know the answer to that.
Preclinically, those experiments haven't been done as to what happens to those types of therapies after treatment with Entinostat in Phase II clinical trial. That was looked at in terms of the balance of the immediate post-treatment as well as overall post-treatment therapies and t hose were quite well-balanced, but the actual response to those individual therapies was not captured. We don't know how they did, we just know what they got.
Okay. Thinking about 5613, a really kind of simple basic science question. What does the Menin MLL1 interaction do in normal tissues? and does that biology inform potentially relevant PD biomarkers?
Yeah. MLL1 actually is not that widely expressed in adult tissues i t tends to evolve in embryonic hematopoiesis. That actually is one of the other reasons why there may be some specificity here, because that amino terminus interacts with Menin, at least the MLL1 interaction you don't see very much in adult tissues.
Okay. Kind of based on the known interaction-based transcriptional effects, is there anything in that biology to inform a good biomarker to show the drug's hitting the target in patients?
Yeah. Maybe Peter, do you want to talk a little bit about that?
Yeah, no, happy to. It's a great question and one obviously that we're interested in t here's been some very nice work published both with Menin inhibitors as well as knockdowns of MLL1 or deletions of the N-terminus. Those all point to certain gene expression signatures, of which several are highlighted and published on the HOX and the MEIS1 and others involved in hematopoietic differentiation and so-
Those all potentially represent genes of interest to look at as well as differentiation markers, as well as chromatin modifications that are mediated by these complexes. Obviously it's a good question and one that's top of our mind as we set up the development to look for these types of assays.
Okay, great t hanks for taking our questions.
Thank you. Now our next question comes from the line of Harshita Polishetty with B. Riley FBR. Your line's now open.
Hi, good afternoon and thank you for taking my questions. In regards to your Menin inhibitor, as a follow-up to the questions that have been asked, this has been historically difficult to target due to the protein-protein interaction.
Briggs, you touched up on the mechanism of action for this molecule in the opening remarks as well as the market opportunity in earlier questions, but I wanted to take a step back and was hoping to gain further insight on the historic failures and challenges with targeting Menin and how 5613 addresses these challenges, and if you have any early insight on the differences between yours and Kura's candidates. Thanks.
Harshita, thanks very much for your question. I will say, when I first heard about the program, and someone told me they had a small molecule that disrupted protein-protein interactions, I was as skeptical as you are. It obviously is not a very standard thing. What's interesting here is that there are nice crystal structures of the actual amino terminus of MLL1 binding to Menin.
It turns out to be a very small four or five amino acid contiguous segment that sits in a pocket of Menin i t's been well-characterized at the crystal structure level and turns out to be highly druggable. I think it is again, we'd be happy to send you some of the references. I think it is one of those "protein-protein interactions" that actually are eminently druggable, and I think we have very good preclinical data to show that.
I think the question on how our molecule compares to the Kura molecule, we don't know exactly which molecule they're taking to the clinic. I think it's a little premature for us to comment on that. We really like our molecule w e're excited about the program. We'll sort of course, be watching them carefully. I think at this stage, it's a little bit hard to know how to compare them.
Great. That helps a lot t hank you, Briggs.
Thank you. Now our next question is a follow-up question from Christopher Marai with Nomura Instinet. Your line's now open.
Hey. Thanks for taking the follow-up. Just on the Menin program, I was wondering, obviously given the pediatric population that's impacted by these diseases, what's your plan for bringing the molecule into pediatrics versus adults, and how should we expect that to progress as you progress the compounds through the clinic? Thank you.
Chris, we are extremely interested in the pediatric population a s I said, the MLL-r ALL is a really unfortunate disease for these little kids and so, w e're working hard on a pediatric formulation that would allow us to dose both kids and infants. As part of our discussions, we're trying to lay out a plan that would allow us to move relatively rapidly and seamlessly from initial Phase I trials in adults into the pediatric population. We'll say more about that, of course, once the IND is approved, and we have an agreement from FDA on what that program will look like, certainly that's our anticipation at this point.
Got it. Thank you very much.
Thank you. I show no further questions at this time. I would like to turn the call back over to Dr. Morrison for closing remarks.
Great. Thank you very much, everybody, for joining us on the call. If you have any additional questions, we'd be happy to take them, and we look forward to further communications from the company t hanks again.
Ladies and gentlemen